The present invention relates to novel imidazo heterocyclic compounds, to the use of these compounds as pharmaceutical compositions, to pharmaceutical compositions comprising the compounds, and to a method of treatment employing these compounds and compositions. The present compounds show a high and selective binding affinity to the histamine H3 receptor indicating histamine H3 receptor antagonistic, inverse agonistic or agonistic activity. As a result, the compounds are useful for the treatment and/or prevention of diseases and disorders related to the histamine H3 receptor.
The existence of the histamine H3 receptor has been known for several years and the receptor is of current interest for the development of new medicaments (see eg Stark, H.; Schlicker, E.; Schunack, W., Drugs Fut. 1996, 21, 507-520; Leurs, R.; Timmerman, H.; Vollinga, R. C., Progress in Drug Research 1995, 45, 107-165). Recently, the human histamine H3 receptor has been cloned, cf Lovenberg, T. W. et al, Molecular Pharmacology, June 1999, 55, 1101-1107. The histamine H3 receptor is a presynaptic autoreceptor located both in the central and the peripheral nervous system, the skin and in organs such as the lung, the intestine, probably the spleen and the gastrointestinal tract. Recent evidence suggests that the H3 receptor show intrinsic, constitutive activity, in vitro as well as in vivo (i.e. it is active in the absence of an agonist; see eg Morisset et al., Nature 2000, 408, 860-864). This activity can be inhibited by compounds acting as inverse agonists.
The histamine H3 receptor has been demonstrated to regulate the release of histamine and also of other neurotransmitters such as serotonin and acetylcholine. A histamine H3 receptor antagonist or inverse agonist would be expected to increase the release of these neurotransmitters in the brain. A histamine H3 receptor agonist, on the contrary, leads to an inhibition of the biosynthesis of histamine and an inhibition of the release of histamine and also of other neurotransmitters such as serotonin and acetylcholine. These findings suggest that histamine H3 receptor agonists, inverse agonists and antagonists could be important mediators of neuronal activity. Accordingly, the histamine H3 receptor is an important target for new therapeutics.
Several publications disclose the preparation and use of histamine H3 agonists and antagonists see eg U.S. Pat. No. 4,767,778 (corresponding to EP 214 058), EP 338 939, WO 93/14070, EP 531 219, EP 458 661, EP 197 840, EP 494 010, WO 91/17146, WO 93/12108, WO 93/12107, WO 93/12093, U.S. Pat. No. 5,578,616 (corresponding to WO 95/14007), WO 96/38142, WO 96/38141, WO 95/11894, WO 93/20061, WO 96/40126, WO 95/06037, WO 92/15567 and WO 94/17058. These imidazole derivatives differ structurally from the present compounds.
Furthermore, Helv. Chim. Acta 1979, 62(2), 507-10 discloses imidazole derivatives. However, they are neither disclosed nor suggested to possess histamine H3 receptor agonistic, inverse agonistic or antagonistic activity.
In view of the art""s interest in histamine H3 receptor agonists, inverse agonists and antagonists, novel compounds which interact with the histamine H3 receptor would be a highly desirable contribution to the art. The present invention provides such a contribution to the art being based on the finding that a novel class of imidazo heterocyclic compounds has a high and specific affinity to the histamine H3 receptor.
Due to their interaction with the histamine H3 receptor, the present compounds are useful in the treatment and/or prevention of a wide range of conditions and disorders in which an interaction with the histamine H3 receptor is beneficial. Thus, the compounds may find use eg in the treatment of diseases of the central nervous system, the peripheral nervous system, the cardiovascular system, the pulmonary system, the gastrointestinal system and the endocrinological system.
The following is a detailed definition of the terms used to describe the compounds of the invention.
xe2x80x9cHalogenxe2x80x9d designates an atom selected from the group consisting of F, Cl, Br and I.
The term xe2x80x9cC1-6-alkylxe2x80x9d in the present context designates a saturated, branched or straight hydrocarbon group having from 1 to 6 carbon atoms. Representative examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, n-hexyl, isohexyl and the like.
The term xe2x80x9cC2-6-alkenylxe2x80x9d as used herein represents a branched or straight hydrocarbon group having from 2 to 6 carbon atoms and at least one double bond. Examples of such groups include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, isopropenyl, 1,3-butadienyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 3-methyl-2-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 2,4-hexadienyl, 5-hexenyl and the like.
The term xe2x80x9cC2-6-alkynylxe2x80x9d as used herein represents a branched or straight hydrocarbon group having from 2 to 6 carbon atoms and at least one triple bond. Examples of such groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 5-hexynyl, 2,4-hexadiynyl and the like.
The term xe2x80x9cC1-6-alkoxyxe2x80x9d in the present context designates a group xe2x80x94Oxe2x80x94C1-6-alkyl wherein C1-6-alkyl is as defined above. Representative examples include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, isopentoxy, neopentoxy, tert-pentoxy, n-hexoxy, isohexoxy and the like.
The term xe2x80x9cC1-6-alkylthioxe2x80x9d in the present context designates a group xe2x80x94Sxe2x80x94C1-6-alkyl wherein C1-6-alkyl is as defined above. Representative examples include, but are not limited to, methylthio, ethylthio, n-propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio, tert-butylthio, n-pentylthio, isopentylthio, neopentylthio, tert-pentylthio, n-hexylthio, isohexylthio and the like.
The term xe2x80x9cC1-6-alkylcarbonylxe2x80x9d in the present context designates a group xe2x80x94C(xe2x95x90O)xe2x80x94C1-6-alkyl wherein C1-6-alkyl is as defined above. Representative examples include, but are not limited to, methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, butylcarbonyl, isobutylcarbonyl, sec-butylcarbonyl, tert-butylcarbonyl, n-pentylcarbonyl, isopentylcarbonyl, neopentylcarbonyl, tert-pentylcarbonyl, n-hexylcarbonyl, isohexylcarbonyl and the like.
The term xe2x80x9cC1-6-alkylsulfonylxe2x80x9d in the present context designates a group xe2x80x94S(xe2x95x90O)2xe2x80x94C1-6-alkyl wherein C1-6-alkyl is as defined above. Representative examples include, but are not limited to, methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, butylsulfonyl, iso-butylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl, n-pentylsulfonyl, isopentylsulfonyl, neopentylsulfonyl, tert-pentylsulfonyl, n-hexylsulfonyl, isohexylsulfonyl and the like.
The term xe2x80x9cC3-10-cycloalkylxe2x80x9d as used herein represents a saturated mono-, bi-, tri- or spirocarbocyclic group having from 3 to 10 carbon atoms. Representative examples are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, bicyclo[3.2.1]octyl, spiro[4.5]decyl, norpinyl, norbonyl, norcaryl, adamantyl and the like.
The term xe2x80x9cC3-10-cycloalkylcarbonylxe2x80x9d as used herein represents a group xe2x80x94C(xe2x95x90O)xe2x80x94C3-10-cycloalkyl wherein C3-10-cycloalkyl is as defined above.
The term xe2x80x9cC3-8-heterocyclylxe2x80x9d as used herein represents a saturated 3 to 8 membered ring containing one or more heteroatoms selected from nitrogen, oxygen and sulfur. Representative examples are pyrrolidyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, aziridinyl, tetrahydrofuranyl and the like.
The term xe2x80x9carylxe2x80x9d as used herein represents a carbocyclic aromatic ring system such as phenyl, biphenyl, naphthyl, anthracenyl, phenanthrenyl, fluorenyl, indenyl, pentalenyl, azulenyl, biphenylenyl and the like. Aryl is also intended to include the partially hydrogenated derivatives of the carbocyclic aromatic systems enumerated above. Non-limiting examples of such partially hydrogenated derivatives are 1,2,3,4-tetrahydronaphthyl, 1,4-dihydronaphthyl and the like.
The term xe2x80x9caroylxe2x80x9d as used herein represents a group xe2x80x94C(xe2x95x90O)-aryl wherein aryl is as defined above.
The term xe2x80x9carylthioxe2x80x9d as used herein represents a group xe2x80x94S-aryl wherein aryl is as defined above.
The term xe2x80x9caryloxyxe2x80x9d as used herein represents a group xe2x80x94O-aryl wherein aryl is as defined above.
The term xe2x80x9carylsulfonylxe2x80x9d as used herein represents a group xe2x80x94S(xe2x95x90O)2-aryl wherein aryl is as defined above.
The term xe2x80x9carylaminoxe2x80x9d as used herein represents a group xe2x80x94NH-aryl wherein aryl is as defined above.
The term xe2x80x9caryl annulated with C3-8-heterocyclylxe2x80x9d as used herein represents a ring system which contains an aryl group as defined herein to which a C3-8-heterocyclyl group as defined herein is attached and which does not fall under the below definiton of heteroaryl. The aryl group and the heterocyclyl group may form fused, bridged or spirocyclic ring systems. Representative examples are 2,3-methylenedioxyphenyl, 3,4-methylenedioxyphenyl, 2,4-methylenedioxyphenyl, 2,5-methylenedioxyphenyl, 3,5-methylenedioxyphenyl, 3,6-methylenedioxyphenyl, chromanyl, isochromanyl, 2,3-ethylenedioxyphenyl, 3,4-ethylenedioxyphenyl, 2,4-ethylenedioxyphenyl, 2,5-ethylenedioxyphenyl, 3,5-ethylenedioxyphenyl, 3,6-ethylenedioxyphenyl and the like.
The term xe2x80x9cheteroarylxe2x80x9d as used herein represents a heterocyclic aromatic ring system containing one or more heteroatoms selected from nitrogen, oxygen and sulfur such as furanyl, thiophenyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5- triazinyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, tetrazolyl, thiadiazinyl, indolyl, isoindolyl, benzofuranyl, benzothiophenyl (thianaphthenyl), indazolyl, benzimidazolyl, benzthiazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, purinyl, quinazolinyl, quinolizinyl, quinolinyl, isoquinolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, azepinyl, diazepinyl, acridinyl and the like. Heteroaryl is also intended to include the partially hydrogenated derivatives of the heterocyclic systems enumerated above. Non-limiting examples of such partially hydrogenated derivatives are 2,3-dihydrobenzofuranyl, pyrrolinyl, pyrazolinyl, indolinyl, oxazolidinyl, oxazolinyl, oxazepinyl and the like.
The term xe2x80x9cheteroaroylxe2x80x9d as used herein represents a group xe2x80x94C(xe2x95x90O)-heteroaryl wherein heteroaryl is as defined above.
The term xe2x80x9cheteroarylthioxe2x80x9d as used herein represents a group xe2x80x94S-heteroaryl wherein heteroaryl is as defined above.
The term xe2x80x9cheteroaryloxyxe2x80x9d as used herein represents a group xe2x80x94O-heteroaryl wherein heteroaryl is as defined above.
The term xe2x80x9cheteroarylsulfonylxe2x80x9d as used herein represents a group xe2x80x94S(xe2x95x90O)2-heteroaryl wherein heteroaryl is as defined above.
The term xe2x80x9cheteroarylaminoxe2x80x9d as used herein represents a group xe2x80x94NH-heteroaryl wherein heteroaryl is as defined above.
xe2x80x9cAryl-C1-6-alkylxe2x80x9d, xe2x80x9cheteroaryl-C1-6-alkylxe2x80x9d etc. means C1-6-alkyl as defined above, substituted by an aryl or heteroaryl as defined above, for example: 
In connection with the terms xe2x80x9cxe2x80x94C(xe2x95x90NOR7)C1-6-alkylxe2x80x9d, xe2x80x9cxe2x80x94C(xe2x95x90NOR7)C3-10-cycloalkylxe2x80x9d, xe2x80x9cxe2x80x94C(xe2x95x90NOR7)arylxe2x80x9d and xe2x80x9cxe2x80x94C(xe2x95x90NOR7)heteroarylxe2x80x9d as used herein it should be understood that the substituents are attached via the carbon atom, for example as follows: 
Certain of the above defined terms may occur more than once in the structural formulae, and upon such occurrence each term shall be defined independently of the other.
The term xe2x80x9coptionally substitutedxe2x80x9d as used herein means that the groups in question are either unsubstituted or substituted with one or more of the substituents specified. When the groups in question are substituted with more than one substituent the substituents may be the same or different.
As used herein, the phrase xe2x80x9ca functional group which can be converted to hydrogen in vivoxe2x80x9d is intended to include any group which upon administering the present compounds to the subjects in need thereof can be converted to hydrogen eg enzymatically or by the acidic environment in the stomach. Non-limiting examples of such groups are acyl, carbamoyl, monoalkylated carbamoyl, dialkylated carbamoyl, alkoxycarbonyl, alkoxyalkyl groups and the like such as C1-6-alkylcarbonyl, aroyl, C1-6-alkylcarbamoyl, di-C1-6-alkylcarbamoyl, C1-6-alkoxycarbonyl and C1-6-alkoxy-C1-6-alkyl.
As used herein, the phrase xe2x80x9cdiseases and disorders related to the histamine H3 receptorxe2x80x9d is intended to include any disease or disorder in which an effect, either antagonistic or agonistic, on the histamine H3 receptor is beneficial.
The present invention relates to a compound of the general formula (I): 
wherein
R1 is hydrogen or a functional group, which can be converted to hydrogen in vivo,
R2 is hydrogen, C1-6-alkyl, C1-6-alkoxy, C1-6-alkylthio, halogen, cyano, trifluoromethyl, hydroxy, thiol or xe2x80x94NR5R6, wherein R5 and R6 independently are hydrogen or C1-6-alkyl,
R3 and R4 independently are hydrogen or C1-6-alkyl, which is optionally substituted with aryl or heteroaryl, which are optionally substituted with one or more substituents selected from nitro, xe2x80x94NR7R8, xe2x80x94S(xe2x95x90O)2NR7R8, xe2x80x94C(xe2x95x90O)NR7R8, hydroxy, halogen, cyano, trifluoromethyl, xe2x80x94OCF3, xe2x80x94OCHF2, xe2x80x94OCH2CHF2, C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, C1-6-alkoxy, C1-6-alkylthio, C1-6-alkylsulfonyl, xe2x80x94C(xe2x95x90O)OR7, C1-6-alkylcarbonyl, xe2x80x94C(xe2x95x90NOR7)C1-6alkyl, C3-10-cycloalkyl, C3-10-cycloalkylcarbonyl, xe2x80x94C(xe2x95x90NOR7)C3-10-cycloalkyl, aryl-C1-6-alkyl, heteroaryl-C1-6-alkyl, arylamino, heteroarylamino, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, xe2x80x94C(xe2x95x90NOR7)aryl, xe2x80x94C(xe2x95x90NOR7)heteroaryl, arylthio, heteroarylthio, aryloxy and heteroaryloxy, wherein R7 and R8 independently are hydrogen or C1-6-alkyl,
m is 0, 1 or 2,
n is 1, 2, 3 or 4,
X is a valence bond, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(xe2x95x90O)xe2x80x94, xe2x80x94S(xe2x95x90O)2xe2x80x94 or xe2x80x94CF2xe2x80x94,
p is 0, 1, 2 or 3,
Y is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(xe2x95x90O)xe2x80x94, xe2x80x94S(xe2x95x90O)2xe2x80x94 or xe2x80x94NR9xe2x80x94, wherein R9 is hydrogen or C1-6-alkyl,
q is 0, 1, 2 or 3,
V is
heteroaryl, aryl, C3-10-cycloalkyl, C3-8-heterocyclyl or aryl annulated with C3-8-heterocyclyl,
which are optionally substituted with one or more substituents selected from nitro, xe2x80x94NR10R11, xe2x80x94S(xe2x95x90O)2NR10R11, xe2x80x94C(xe2x95x90O)NR10R11, hydroxy, halogen, cyano, trifluoromethyl, xe2x80x94OCF3, xe2x80x94OCHF2, xe2x80x94OCH2CHF2, C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, C1-6-alkoxy, C1-6-alkylthio, C1-6-alkylsulfonyl, xe2x80x94C(xe2x95x90O)OR10, C1-6-alkylcarbonyl, xe2x80x94C(xe2x95x90NOR10)C1-6-alkyl, oxo, C3-10-cycloalkyl, C3-10-cycloalkylcarbonyl, xe2x80x94C(xe2x95x90NOR10)C3-10-cycloalkyl, heteroaryl-C1-6-alkyl, arylamino, heteroarylamino, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, xe2x80x94C(xe2x95x90NOR10)aryl, xe2x80x94C(xe2x95x90NOR10)heteroaryl, arylthio, heteroarylthio, and heteroaryloxy, wherein R10 and R11 independently are hydrogen or C1-6-alkyl,
aryl-C1-6-alkyl, aryl or aryloxy, which are optionally substituted with one or more substituents selected from
nitro, hydroxy, C1-6-alkyl, C1-6-alkoxy, cyano, trifluoromethyl, xe2x80x94OCF3, halogen
C1-6-alkyl, C2-6-alkenyl or C2-6-alkynyl,
which are optionally substituted with one or more substituents selected from C3-10-cycloalkyl, aryl, C3-8-heterocyclyl and heteroaryl, which are optionally substituted with one or more substituents selected from
nitro, xe2x80x94NR12R13, xe2x80x94S(xe2x95x90O)2NR12R13, xe2x80x94C(xe2x95x90O)NR12R13, hydroxy, halogen, cyano, trifluoromethyl, xe2x80x94OCF3, xe2x80x94OCHF2, xe2x80x94OCH2CHF2, C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, C1-6-alkoxy, C1-6-alkylthio, C1-6-alkylsulfonyl, xe2x80x94C(xe2x95x90O)OR12, C1-6-alkylcarbonyl, xe2x80x94C(xe2x95x90NOR12)C1-6-alkyl, C3-10-cycloalkyl, C3-10-cycloalkylcarbonyl, xe2x80x94C(xe2x95x90NOR12)C3-10-cycloalkyl, aryl-C1-6-alkyl, heteroaryl-C1-6-alkyl, arylamino, heteroarylamino, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, xe2x80x94C(xe2x95x90NOR12)aryl, xe2x80x94C(xe2x95x90NOR12)heteroaryl, arylthio, heteroarylthio, aryloxy and heteroaryloxy, wherein R12 and R13 independently are hydrogen or C1-6-alkyl,
with the proviso that when
R1, R2, R3 and R4 are hydrogen, X is a valence bond, m is 0, n is 3, p is 0 and Y is xe2x80x94Sxe2x80x94, xe2x80x94(CH2)qxe2x80x94V must not be xe2x80x94(CH2)2xe2x80x94NH2,
as well as any optical or geometric isomer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof.
In another aspect the present invention relates to a compound of the general formula (Ixe2x80x3): 
wherein
R1 is hydrogen or a functional group, which can be converted to hydrogen in vivo,
R2 is hydrogen, C1-6-alkyl, C1-6-alkoxy, C1-6-alkylthio, halogen, cyano, trifluoromethyl, hydroxy, thiol or xe2x80x94NR5R6, wherein R5 and R6 independently are hydrogen or C1-6-alkyl,
R3 and R4 independently are hydrogen or C1-6-alkyl, which is optionally substituted with aryl or heteroaryl, which are optionally substituted with one or more substituents selected from nitro, xe2x80x94NR7R8, xe2x80x94S(xe2x95x90O)2R7R8, xe2x80x94C(xe2x95x90O)R7R8, hydroxy, halogen, cyano, trifluoromethyl, xe2x80x94OCF3, xe2x80x94OCHF2, xe2x80x94OCH2CHF2, C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, C1-6-alkoxy, C1-6-alkylthio, C1-6-alkylsulfonyl, xe2x80x94C(xe2x95x90O)OR7, C1-6-alkylcarbonyl, xe2x80x94C(xe2x95x90NOR7)C1-6-alkyl, C3-10-cycloalkyl, C3-10-cycloalkylcarbonyl, xe2x80x94C(xe2x95x90NOR7)C3-10-cycloalkyl, aryl-C1-6-alkyl, heteroaryl-C1-6-alkyl, arylamino, heteroarylamino, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, xe2x80x94C(xe2x95x90NOR7)aryl, xe2x80x94C(xe2x95x90NOR7)heteroaryl, arylthio, heteroarylthio, aryloxy and heteroaryloxy, wherein R7 and R8 independently are hydrogen or C1-6-alkyl,
m is 0, 1 or 2,
n is 1, 2, 3 or 4,
X is a valence bond, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(xe2x95x90O)xe2x80x94, xe2x80x94S(xe2x95x90O)2xe2x80x94 or xe2x80x94CF2xe2x80x94,
p is 0, 1, 2 or 3,
Y is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(xe2x95x90O)xe2x80x94, xe2x80x94S(xe2x95x90O)2xe2x80x94 or xe2x80x94NR9xe2x80x94, wherein R9 is hydrogen or C1-6-alkyl,
q is 0, 1, 2 or 3,
V is
heteroaryl, aryl, C3-10-cycloalkyl, C3-8-heterocyclyl or aryl annulated with C3-8-heterocyclyl,
which are optionally substituted with one or more substituents selected from nitro, xe2x80x94NR10R11, xe2x80x94S(xe2x95x90O)2NR10R11, xe2x80x94C(xe2x95x90O)NR10R11, hydroxy, halogen, cyano, trifluoromethyl, xe2x80x94OCF3, xe2x80x94OCHF2, xe2x80x94OCH2CHF2, C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, C1-6-alkoxy, C1-6-alkylthio, C1-6-alkylsulfonyl, xe2x80x94C(xe2x95x90O)OR10, C1-6-alkylcarbonyl, xe2x80x94C(xe2x95x90NOR10)C1-6-alkyl, C3-10-cycloalkyl, C3-10-cycloalkylcarbonyl, xe2x80x94C(xe2x95x90NOR10)C3-10-cycloalkyl, aryl-C1-6-alkyl, heteroaryl-C1-6-alkyl, arylamino, heteroarylamino, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, xe2x80x94C(xe2x95x90NOR10)aryl, xe2x80x94C(xe2x95x90NOR10)heteroaryl, arylthio, heteroarylthio, aryloxy and heteroaryloxy, wherein R10 and R11 independently are hydrogen or C1-6-alkyl,
C1-6-alkyl, C2-6-alkenyl or C2-6-alkynyl,
which are optionally substituted with one or more substituents selected from C3-10-cycloalkyl, aryl, C3-8-heterocyclyl and heteroaryl, which are optionally substituted with one or more substituents selected from nitro, xe2x80x94NR12R13, xe2x80x94S(xe2x95x90O)2NR12R13, xe2x80x94C(xe2x95x90O)NR12R13, hydroxy, halogen, cyano, trifluoromethyl, xe2x80x94OCF3, xe2x80x94OCHF2, xe2x80x94OCH2CHF2, C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, C1-6-alkoxy, C1-6-alkylthio, C1-6-alkylsulfonyl, xe2x80x94C(xe2x95x90O)OR12, C1-6-alkylcarbonyl, xe2x80x94C(xe2x95x90NOR12)C1-6-alkyl, C3-10-cycloalkyl, C3-10-cycloalkylcarbonyl, xe2x80x94C(xe2x95x90NOR12)C3-10-cycloalkyl, aryl-C1-6-alkyl, heteroaryl-C1-6-alkyl, arylamino, heteroarylamino, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, xe2x80x94C(xe2x95x90NOR12)aryl, xe2x80x94C(xe2x95x90NOR12)heteroaryl, arylthio, heteroarylthio, aryloxy and heteroaryloxy, wherein R12 and R13 independently are hydrogen or C1-6-alkyl,
with the proviso that when
R1, R2, R3 and R4 are hydrogen, X is a valence bond, m is 0, n is 3, p is 0 and Y is xe2x80x94Sxe2x80x94, xe2x80x94(CH2)qxe2x80x94V must not be xe2x80x94(CH2)2xe2x80x94NH2,
as well as any optical or geometric isomer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof.
Preferably, R1 is hydrogen.
R2 is also preferably hydrogen.
Preferably, R3 and R4 are both hydrogen.
In a preferred embodiment m is 1 and n is 2.
In another preferred embodiment m is 0 and n is 3 or 4.
In yet another preferred embodiment m is 1 and n is 1.
p is preferably 1 or 2.
X is preferably a valence bond or xe2x80x94Oxe2x80x94.
Y is preferably xe2x80x94Oxe2x80x94.
q is preferably 0 or 1.
In a preferred embodiment V is selected from heteroaryl, aryl and aryl annulated with C3-8-heterocyclyl, which are optionally substituted as defined for formula (I).
Preferably, V is selected from aryl and aryl annulated with C3-8-heterocyclyl, which are optionally substituted as defined as for formula (I).
More preferably, V is selected from phenyl, naphthyl, tetrahydronaphthyl and 3,4-methylenedioxyphenyl, which are optionally substituted as defined for formula (I).
Even more preferably, V is selected from phenyl and naphthyl, which are optionally substituted as defined for formula (I).
Preferably, V is unsubstituted or substituted with one or two substituents independently selected from
halogen, C3-10-cycloalkylcarbonyl, cyano, C1-6-alkylcarbonyl, xe2x80x94C(xe2x95x90O)OR10, C1-6-alkyl, C1-6-alkoxy, xe2x80x94CF3 and xe2x80x94OCF3, wherein R10 is as defined for formula (I) above,
aryl-C1-6-alkyl, aryl and aryloxy, which are optionally substituted as defined for formula (I) above.
More preferably, V is unsubstituted or substituted with one or two substituents independently selected from
halogen, C3-10-cycloalkylcarbonyl, cyano, C1-6-alkylcarbonyl, xe2x80x94C(xe2x95x90O)OR10, C1-6-alkyl, C1-6-alkoxy, xe2x80x94CF3 and xe2x80x94OCF3, wherein R10 is as defined for formula (I) above,
phenyl-C1-6-alkyl, phenyl and phenoxy, which are optionally substituted as defined for formula (I) above.
Even more preferably, V is unsubstituted or substituted with one or two substituents independently selected from phenyl, phenoxy and trifluoromethyl.
In another preferred embodiment V is C1-6-alkyl or C2-6-alkenyl, which is optionally substituted as defined for formula (I) above.
Preferably, V is C1-6-alkyl or C2-6-alkenyl, which is substituted with aryl, which is optionally substituted as defined for formula (I) above.
More preferably, V is C1-6-alkyl or C2-6-alkenyl, which is substituted with phenyl, which is optionally substituted as defined for formula (I) above.
In a preferred embodiment the invention relates to a compound of the general formula (Ie): 
wherein R1, R2, R3, R4 and V are as defined for formula (I) or in any of the above preferred embodiments.
In another preferred embodiment the invention relates to a compound of the general formula (If): 
wherein R1, R2, R3, R4 and V are as defined are as defined for formula (I) or in any of the above preferred embodiments.
In still another preferred embodiment the invention relates to a compound of the general formula (Ig): 
wherein R1, R2, R3, R4 and V are as defined are as defined for formula (I) or in any of the above preferred embodiments.
In yet another preferred embodiment the invention relates to a compound of the general formula (Ih): 
wherein R1, R2, R3, R4 and V are as defined are as defined for formula (I) or in any of the above preferred embodiments.
In a further preferred embodiment the invention relates to a compound of the general formula (Ii): 
wherein R1, R2, R3, R4 and V are as defined are as defined for formula (I) or in any of the above preferred embodiments.
The following compounds are within the scope of the present invention:
2-(4,5,6,7-tetrahydro-1H-benzimidazol-5-ylmethoxy)benzonitrile,
5-(4-chlorophenoxymethyl)-4,5,6,7-tetrahydro-1H-benzimidazole,
cyclopropyl-(4-(4,5,6,7-tetrahydro-1H-benzimidazol-5-ylmethoxy)methanone,
5-(naphth-1-yloxymethyl)-4,5,6,7-tetrahydro-1H-benzimidazole,
5-(naphth-2-yloxymethyl)-4,5,6,7-tetrahydro-1H-benzimidazole,
5-(5,6,7,8-tetrahydronaphth-2-yloxymethyl)-4,5,6,7-tetrahydro-1H-benzimidazole,
5-(3-chlorophenoxymethyl)-4,5,6,7-tetrahydro-1H-benzimidazole,
3-(4,5,6,7-tetrahydro-1H-benzimidazol-5-ylmethoxy)benzonitrile,
5-(4-benzylphenoxymethyl)-4,5,6,7-tetrahydro-1H-benzimidazole,
5-(3,4-methylenedioxyphenoxymethyl)-4,5,6,7-tetrahydro-1H-benzimidazole,
4-(4,5,6,7-tetrahydro-1H-benzimidazol-5-ylmethoxy)benzoic acid ethyl ester,
5-(2,4-difluorophenoxymethyl)-4,5,6,7-tetrahydro-1H-benzimidazole,
5-(2-chlorophenoxymethyl)-4,5,6,7-tetrahydro-1H-benzimidazole,
5-(2-iodophenoxymethyl)-4,5,6,7-tetrahydro-1H-benzimidazole,
5-(2-trifluoromethyl-phenoxymethyl)-4,5,6,7-tetrahydro-1H-benzimidazole,
5-(2-fluorophenoxymethyl)-4,5,6,7-tetrahydro-1H-benzimidazole,
5-(3-trifluoromethoxyphenoxymethyl)-4,5,6,7-tetrahydro-1H-benzimidazole,
5-(biphenyl-3-yloxymethyl)-4,5,6,7-tetrahydro-1H-benzimidazole,
5-(3-trifluoromethylphenoxymethyl)-4,5,6,7-tetrahydro-1H-benzimidazole,
5-(2,6-difluorophenoxymethyl)-4,5,6,7-tetrahydro-1H-benzimidazole,
5-(4-trifluoromethoxyphenoxymethyl)-4,5,6,7-tetrahydro-1H-benzimidazole,
4-(2-ethylphenoxymethyl)-4,5,6,7-tetrahydro-1H-benzimidazole,
4-(4-cyanophenoxymethyl)-4,5,6,7-tetrahydro-1H-benzimidazole,
4-(1-naphthyloxymethyl)-4,5,6,7-tetrahydro-1H-benzimidazole,
4-(2-chlorophenoxymethyl)-4,5,6,7-tetrahydro-1H-benzimidazole,
4-(2-chlorophenoxymethyl)-1,4,5,6,7,8-hexahydrocycloheptaimidazole,
4-(2,4-difluorophenoxymethyl)-4,5,6,7-tetrahydro-1H-benzimidazole,
4-(2,4-difluorophenoxymethyl)-1,4,5,6,7,8-hexahydrocycloheptaimidazole,
4-(3-acetylphenoxymethyl)-1,4,5,6,7,8-hexahydrocycloheptaimidazole,
5-[2-(2,4-dichlorophenoxy)ethyl]-4,5,6,7-tetrahydro-1H-benzimidazole,
5-[2-(3-phenoxyphenoxy)ethyl]-4,5,6,7-tetrahydro-1H-benzimidazole,
5-[2-(naphth-1-yloxy)ethyl]-4,5,6,7-tetrahydro-1H-benzimidazole,
5-[2-(biphenyl-2-yloxy)ethyl]-4,5,6,7-tetrahydro-1H-benzimidazole,
5-[3-(4-chlorophenoxy)propyl]-4,5,6,7-tetrahydro-1H-benzimidazole,
4-[3-(4,5,6,7-tetrahydro-1H-benzimidazol-5-yl)propoxy]benzonitrile,
5-(2-benzyloxyethyl)-4,5,6,7-tetrahydro-1H-benzimidazole,
5-benzyloxy-4,5,6,7-tetrahydro-1H-benzimidazole,
5-((biphenyl-2-yl)methoxymethyl)-4,5,6,7-tetrahydro-1H-benzimidazole,
5-((1-naphthyl)methoxymethyl)-4,5,6,7-tetrahydro-1H-benzimidazole,
5-(4-trifluoromethylbenzyloxymethyl)-4,5,6,7-tetrahydro-1H-benzimidazole,
5-((3-(trifluoromethyl)benzyloxy)methyl)-4,5,6,7-tetrahydro-1H-benzimidazole,
5-((2-phenoxybenzyloxy)methyl)-4,5,6,7-tetrahydro-1H-benzimidazole,
6-phenoxymethyl-3,4,6,7-tetrahydropyrano[3,4-d]imidazole,
5-allyloxymethyl-4,5,6,7-tetrahydro-1H-benzimidazole,
5-(((2-naphthyl)methoxy)methyl)-4,5,6,7-tetrahydro-1H-benzimidazole,
5-(2-chloro-5-trifluoromethylbenzyloxymethyl)-4,5,6,7-tetrahydro-1H-benzimidazole,
(E)-5-(3-phenylallyloxymethyl)-4,5,6,7-tetrahydro-1H-benzimidazole,
5-((biphenyl-4-yl)methoxymethyl)-4,5,6,7-tetrahydro-1H-benzimidazole,
5-(3-phenylpropoxymethyl)-4,5,6,7-tetrahydro-1H-benzimidazole,
5-(2-chloro-3-(trifluoromethyl)benzyloxymethyl)-4,5,6,7-tetrahydro-1H-benzimidazole,
3-(((4,5,6,7-tetrahydro-1H-benzimidazol-5-yl)methoxy)methyl)benzonitrile,
5-(4-phenylbutoxymethyl)-4,5,6,7-tetrahydro-1H-benzimidazole,
5-[(2-(2,4-dichlorophenoxy)benzyloxy)methyl]-4,5,6,7-tetrahydro-1H-benzimidazole
5-[2-(4-fluorobenzyl)benzyloxymethyl]-4,5,6,7-tetrahydro-1H-benzimidazole,
5-[2-(3-(trifluoromethoxy)phenoxy)benzyloxymethyl]-4,5,6,7-tetrahydro-1H-benzimidazole,
5-((5-phenylpentyloxy)methyl)-4,5,6,7-tetrahydro-1H-benzimidazole,
4-(1,4,5,6,7,8-hxahydrocycloheptaimidazol-4-ylmethoxy)benzonitrile,
4-(4-trifluoromethoxyphenoxymethyl)-4,5,6,7-tetrahydro-1H-benzimidazole,
4-(4-trifluoromethylphenoxymethyl)-4,5,6,7-tetrahydro-1H-benzimidazole,
3,5-dimethyl-4-(4,5,6,7-tetrahydro-1H-benzimidazol-4-ylmethoxy)benzonitrile,
3-chloro-4-(4,5,6,7-tetrahydro-1H-benzimidazol-4-ylmethoxy)benzonitrile,
3-(4,5,6,7-tetrahydro-1H-benzimidazol-4-ylmethoxy)benzonitrile,
cyclopropyl-[4-(4,5,6,7-tetrahydro-1H-benzimidazol-4-ylmethoxy)phenyl]methanone,
3-methoxy-4-(4,5,6,7-tetrahydro-1H-benzimidazol-4-ylmethoxy)benzonitrile,
5-(4,5,6,7-tetrahydro-1H-benzimidazol-4-ylmethoxy)-3,4-dihydro-2H-naphthalen-1-one,
4-(4-chlorophenoxymethyl)-4,5,6,7-tetrahydro-1H-benzimidazole,
[5-chloro-2-(4,5,6,7-tetrahydro-1H-benzimidazol-4-ylmethoxy)phenyl]phenylmethanone,
as well as any optical or geometric isomer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof.
The compounds of the present invention may have one or more asymmetric centres and it is intended that any optical isomers, as separated, pure or partially purified optical isomers or racemic mixtures thereof are included within the scope of the invention.
Furthermore, when a double bond or a fully or partially saturated ring system is present in the molecule geometric isomers may be formed. It is intended that any geometric isomers, as separated, pure or partially purified geometric isomers or mixtures thereof are included within the scope of the invention. Likewise, molecules having a bond with restricted rotation may form geometric isomers. These are also intended to be included within the scope of the present invention.
Furthermore, some of the compounds of the present invention may exist in different tautomeric forms and it is intended that any tautomeric forms, which the compounds are able to form, are included within the scope of the present invention.
The present invention also encompasses pharmaceutically acceptable salts of the present compounds. Such salts include pharmaceutically acceptable acid addition salts, pharmaceutically acceptable metal salts, ammonium and alkylated ammonium salts. Acid addition salts include salts of inorganic acids as well as organic acids. Representative examples of suitable inorganic acids include hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, nitric acids and the like. Representative examples of suitable organic acids include formic, acetic, trichloroacetic, trifluoroacetic, propionic, benzoic, cinnamic, citric, fumaric, glycolic, lactic, maleic, malic, malonic, mandelic, oxalic, picric, pyruvic, salicylic, succinic, methanesulfonic, ethanesulfonic, tartaric, ascorbic, pamoic, bismethylene salicylic, ethanedisulfonic, gluconic, citraconic, aspartic, stearic, palmitic, EDTA, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, p-toluenesulfonic acids and the like. Further examples of pharmaceutically acceptable inorganic or organic acid addition salts include the pharmaceutically acceptable salts listed in J. Pharm. Sci. 1977, 66, 2, which is incorporated herein by reference. Examples of metal salts include lithium, sodium, potassium, magnesium salts and the like. Examples of ammonium and alkylated ammonium salts include ammonium, methylammonium, dimethylammonium, trimethylammonium, ethylammonium, hydroxyethylammonium, diethylammonium, butylammonium, tetramethylammonium salts and the like.
Also intended as pharmaceutically acceptable acid addition salts are the hydrates, which the present compounds are able to form.
The acid addition salts may be obtained as the direct products of compound synthesis. In the alternative, the free base may be dissolved in a suitable solvent containing the appropriate acid, and the salt isolated by evaporating the solvent or otherwise separating the salt and solvent.
The compounds of the present invention may form solvates with standard low molecular weight solvents using methods well known to the person skilled in the art. Such solvates are also contemplated as being within the scope of the present invention.
The invention also encompasses prodrugs of the present compounds, which on administration undergo chemical conversion by metabolic processes before becoming active pharmacological substances. In general, such prodrugs will be functional derivatives of the present compounds, which are readily convertible in vivo into the required compound of the formula (I). Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in xe2x80x9cDesign of Prodrugsxe2x80x9d, ed. H. Bundgaard, Elsevier, 1985.
The invention also encompasses active metabolites of the present compounds.
The compounds of the present invention interact with the histamine H3 receptor and are accordingly useful for the treatment and/or prevention of a wide variety of conditions and disorders in which histamine H3 receptor interactions are beneficial.
Accordingly, in another aspect the present invention relates to compounds of the general formula (Ixe2x80x2): 
wherein
R1 is hydrogen or a functional group, which can be converted to hydrogen in vivo,
R2 is hydrogen, C1-6-alkyl, C1-6-alkoxy, C1-6-alkylthio, halogen, cyano, trifluoromethyl, hydroxy, thiol or xe2x80x94NR5R6, wherein R5 and R6 independently are hydrogen or C1-6-alkyl,
R3 and R4 independently are hydrogen or C1-6-alkyl, which is optionally substituted with aryl or heteroaryl, which are optionally substituted with one or more substituents selected from nitro, xe2x80x94NR7R8, xe2x80x94S(xe2x95x90O)2NR7R8, xe2x80x94C(xe2x95x90O)NR7R8, hydroxy, halogen, cyano, trifluoromethyl, xe2x80x94OCF3, xe2x80x94OCHF2, xe2x80x94OCH2CHF2, C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, C1-6-alkoxy, C1-6-alkylthio, C1-6-alkylsulfonyl, xe2x80x94C(xe2x95x90O)OR7, C1-6-alkylcarbonyl, xe2x80x94C(xe2x95x90NOR7)C1-6-alkyl, C3-10-cycloalkyl, C3-10-cycloalkylcarbonyl, xe2x80x94C(xe2x95x90NOR7)C3-10-cycloalkyl, aryl-C1-6-alkyl, heteroaryl-C1-6-alkyl, arylamino, heteroarylamino, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, xe2x80x94C(xe2x95x90NOR7)aryl, xe2x80x94C(xe2x95x90NOR7)heteroaryl, arylthio, heteroarylthio, aryloxy and heteroaryloxy, wherein R7 and R8 independently are hydrogen or C1-6-alkyl,
m is 0, 1 or 2,
n is 1, 2, 3 or 4,
X is a valence bond, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(xe2x95x90O)xe2x80x94, xe2x80x94S(xe2x95x90O)2xe2x80x94 or xe2x80x94CF2xe2x80x94,
p is 0, 1, 2 or 3,
Y is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(xe2x95x90O)xe2x80x94, xe2x80x94S(xe2x95x90O)2xe2x80x94 or xe2x80x94NR9xe2x80x94, wherein R9 is hydrogen or C1-6-alkyl,
q is 0, 1, 2 or 3,
V is
heteroaryl, aryl, C3-10-cycloalkyl, C3-8-heterocyclyl or aryl annulated with C3-8-heterocyclyl,
which are optionally substituted with one or more substituents selected from nitro, xe2x80x94NR10R11, xe2x80x94S(xe2x95x90O)2NR10R11, xe2x80x94C(xe2x95x90O)NR10R11, hydroxy, halogen, cyano, trifluoromethyl, xe2x80x94OCF3, xe2x80x94OCHF2, xe2x80x94OCH2CHF2, C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, C1-6-alkoxy, C1-6-alkylthio, C1-6-alkylsulfonyl, xe2x80x94C(xe2x95x90O)OR10, xe2x80x94C(xe2x95x90O)R10, C1-6-alkylcarbonyl, xe2x80x94C(xe2x95x90NOR10)C1-6-alkyl, oxo, C3-10-cycloalkyl, C3-10-cycloalkylcarbonyl, xe2x80x94C(xe2x95x90NOR10)-C3-10-cycloalkyl, heteroaryl-C1-6-alkyl, arylamino, heteroarylamino, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, xe2x80x94C(xe2x95x90NOR10)aryl, xe2x80x94C(xe2x95x90NOR10)heteroaryl, arylthio, heteroarylthio, and heteroaryloxy, wherein R10 and R11 independently are hydrogen or C1-6-alkyl,
aryl-C1-6-alkyl, aryl or aryloxy, which are optionally substituted with one or more substituents selected from
nitro, hydroxy, C1-6-alkyl, C1-6-alkoxy, cyano, trifluoromethyl, xe2x80x94OCF3, halogen
C1-6-alkyl, C2-6-alkenyl or C2-6-alkynyl,
which are optionally substituted with one or more substituents selected from C3-10-cycloalkyl, aryl, C3-8-heterocyclyl and heteroaryl, which are optionally substituted with one or more substituents selected from
nitro, xe2x80x94NR12R13, xe2x80x94S(xe2x95x90O)2NR12R13, xe2x80x94C(xe2x95x90O)NR12R13, hydroxy, halogen, cyano, trifluoromethyl, xe2x80x94OCF3, xe2x80x94OCHF2, xe2x80x94OCH2CHF2, C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, C1-6-alkoxy, C1-6-alkylthio, C1-6-alkylsulfonyl, xe2x80x94C(xe2x95x90O)OR12, C1-6-alkylcarbonyl, xe2x80x94C(xe2x95x90NOR12)C1-6-alkyl, C3-10-cycloalkyl, C3-10-cycloalkylcarbonyl, xe2x80x94C(xe2x95x90NOR12)C3-10-cycloalkyl, aryl-C1-6-alkyl, heteroaryl-C1-6-alkyl, arylamino, heteroarylamino, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, xe2x80x94C(xe2x95x90NOR12)aryl, xe2x80x94C(xe2x95x90NOR12)heteroaryl, arylthio, heteroarylthio, aryloxy and heteroaryloxy, wherein R12 and R13 independently are hydrogen or C1-6-alkyl, as well as any optical or geometric isomer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof as a pharmaceutical composition.
The invention also relates to pharmaceutical compositions comprising, as an active ingredient, at least one compound of the formula (Ixe2x80x2) or any optical or geometric isomer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt hereof together with one or more pharmaceutically acceptable carriers or diluents.
Furthermore, the invention relates to the use of a compound of the general formula (Ixe2x80x2) or any optical or geometric isomer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof for the preparation of a pharmaceutical composition for the treatment and/or prevention of diseases and disorders related to the histamine H3 receptor.
In still another aspect, the invention relates to a method for the treatment and/or prevention of diseases and disorders related to the histamine H3 receptor the method comprising administering to a subject in need thereof an effective amount of a compound of the formula (Ixe2x80x2) or any optical or geometric isomer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same.
In one aspect the invention relates to compounds with histamine H3 receptor antagonistic activity or inverse agonistic activity which may accordingly be useful in the treatment of a wide range of conditions and disorders in which histamine H3 receptor blockade is beneficial.
In another aspect the invention relates to compounds with histamine H3 receptor agonistic activity and which may accordingly be useful in the treatment of a wide range of conditions and disorders in which histamine H3 receptor activation is beneficial.
In a preferred embodiment of the invention the present compounds are used for the preparation of a pharmaceutical composition for the reduction of weight.
In a preferred embodiment of the invention the present compounds are used for the preparation of a pharmaceutical composition for the treatment and/or prevention of overweight or obesity.
In another preferred embodiment of the invention the present compounds are used for the preparation of a pharmaceutical composition for the suppression of appetite or satiety induction.
In a further preferred embodiment of the invention the present compounds are used for the preparation of a pharmaceutical composition for the prevention and/or treatment of disorders and diseases related to overweight or obesity such as atherosclerosis, hypertension, IGT (impaired glucose tolerance), diabetes, especially Type 2 diabetes (NIDDM (non-insulin dependent diabetes mellitus)), dyslipidaemia, coronary heart disease, gallbladder disease, osteoarthritis and various types of cancer such as endometrial, breast, prostate and colon cancers.
In yet a further preferred embodiment of the invention the present compounds are used for the preparation of a pharmaceutical composition for the prevention and/or treatment of eating disorders such as bulimia and binge eating.
In a further preferred embodiment of the invention the present compounds are used for the preparation of a pharmaceutical composition for the treatment and/or prevention of IGT.
In a further preferred embodiment of the invention the present compounds are used for the preparation of a pharmaceutical composition for the treatment and/or prevention of Type 2 diabetes.
In another preferred embodiment of the invention the present compounds are used for the preparation of a pharmaceutical composition for the delaying or prevention of the progression from IGT to Type 2 diabetes.
In a further preferred embodiment of the invention the present compounds are used for the preparation of a pharmaceutical composition for the delaying or prevention of the progression from non-insulin requiring Type 2 diabetes to insulin requiring Type 2 diabetes.
The compounds of the present invention may also be used for the treatment of air-way disorders such as asthma, as anti-diarrhoeals and for the modulation of gastric acid secretion.
Furthermore, the compounds of the present invention may be used for the treatment of diseases associated with the regulation of sleep and wakefulness and for the treatment of narcolepsy and attention deficit disorders.
Moreover, the compounds of the invention may be used as CNS stimulants or as sedatives.
The present compounds may also be used for the treatment of conditions associated with epilepsy. Additionally, the present compounds may be used for the treatment of motion sickness and vertigo. Furthermore, they may be useful as regulators of hypothalamohypophyseal secretion, antidepressants, modulators of cerebral circulation, and in the treatment of irritable bowel syndrome.
Further, the compounds of the present invention may be used for the treatment of dementia and Alzheimer""s disease.
The compounds of the present invention may also be useful for the treatment of allergic rhinitis, ulcer or anorexia.
The compounds of the present invention may furthermore be useful for the treatment of migraine, see R. L. McLeod et al., The Journal of Pharmacology and Experimental Therapeutics 287 (1998), 43-50, and for the treatment of myocardial infarction, see C. J. Mackins and R. Levi, Expert Opinion on Investigational Drugs 9 (2000), 2537-2542.
The present novel compounds may also interact with the vanilloid receptors, the serotonin receptors, and the adrenergic receptors and may be useful for the treatment of diseases associated with these receptors. Hence, the compounds of the present invention may be vanilloid receptor agonists, and thus be useful for the treatment of obesity by enhancement of the metabolic rate and energy expenditure. Further, by virtue of their interaction with the vanilloid receptor the compounds of the present invention may be useful for the treatment of pain or neurogenic inflammation or inflammatory painful conditions.
In a further preferred embodiment of the invention the present compounds are used for the preparation of a pharmaceutical composition for the treatment and/or prevention of diseases and disorders related to the vanilloid receptor, such as for the treatment and/or prevention of pain, neurogenic inflammation or obesity.
Furthermore, the present compounds may interact with the 5-HT3 receptor (serotonin-3-receptor), the compounds of the present invention may be useful as antiemetics, in particular the chemotherapy-induced emesis. Further potential applications of 5-HT3 antagonists include treatment of central nervous system disorders such as anxiety, schizophrenia, drug abuse and withdrawal symptoms, and pathological and age-associated amnesia.
In a further preferred embodiment of the invention the present compounds are used for the preparation of a pharmaceutical composition for the treatment and/or prevention of diseases and disorders related to the serotonin-3 receptor (5-HT3), such as for the treatment of emesis.
Furthermore, the present compounds may interact with the adrenergic alpha-2-receptor and thus be useful for the treatment of hypertension and of conditions associated with overexpression or hypersensitization of the adrenergic alpha-2 receptor, especially obesity, withdrawal symptoms to an adrenergic alpha-2 agonist, neurological disorders (especially orthostatic hypotension), multiple system atrophy, diabetes mellitus, benign prostatic hyperplasia or drug induced sensitization of the adrenergic alpha-2 receptor. Moreover, the compounds of the present invention, by virtue of their interaction with the adrenergic alpha-2 receptor, may be useful as sedatives and hypnotics (sleep inducing agents) or as stimulants.
In a further preferred embodiment of the invention the present compounds are used for the preparation of a pharmaceutical composition for the treatment and/or prevention of diseases and disorders related to the alpha-2 adrenergic receptor, such as for use as a sleep inducing agent.
In a further aspect of the invention the present compounds are combined with diet and/or exercise.
In a further aspect of the invention the present compounds may be administered in combination with one or more further pharmacologically active substances in any suitable ratios. Such further active agents may be selected from antiobesity agents, antidiabetics, antihypertensive agents, agents for the treatment and/or prevention of complications resulting from or associated with diabetes and agents for the treatment and/or prevention of complications and disorders resulting from or associated with obesity.
Thus, in a further aspect of the invention the present compounds may be administered in combination with one or more antiobesity agents or appetite regulating agents.
Such agents may be selected from the group consisting of CART (cocaine amphetamine regulated transcript) agonists, NPY (neuropeptide Y) antagonists, MC4 (melanocortin 4) agonists, MC3 (melanocortin 3) agonists, orexin antagonists, TNF (tumor necrosis factor) agonists, CRF (corticotropin releasing factor) agonists, CRF BP (corticotropin releasing factor binding protein) antagonists, urocortin agonists, xcex23 agonists, MSH (melanocyte-stimulating hormone) agonists, MCH (melanocyte-concentrating hormone) antagonists, CCK (cholecystokinin) agonists, serotonin re-uptake inhibitors, serotonin and noradrenaline re-uptake inhibitors, mixed serotonin and noradrenergic compounds, 5HT (serotonin) agonists, bombesin agonists, galanin antagonists, growth hormone, growth factors such as prolactin or placental lactogen, growth hormone releasing compounds, TRH (thyreotropin releasing hormone) agonists, UCP 2 or 3 (uncoupling protein 2 or 3) modulators, leptin agonists, DA agonists (bromocriptin, doprexin), lipase/amylase inhibitors, PPAR (peroxisome proliferator-activated receptor) modulators, RXR (retinoid X receptor) modulators, TR xcex2 agonists, AGRP (Agouti related protein) inhibitors, opioid antagonists (such as naltrexone), exendin-4, GLP-1 and ciliary neurotrophic factor.
In one embodiment of the invention the antiobesity agent is leptin.
In another embodiment the antiobesity agent is dexamphetamine or amphetamine.
In another embodiment the antiobesity agent is fenfluramine or dexfenfluramine.
In still another embodiment the antiobesity agent is sibutramine.
In a further embodiment the antiobesity agent is orlistat.
In another embodiment the antiobesity agent is mazindol or phentermine.
In still another embodiment the antiobesity agent is phendimetrazine, diethylpropion, fluoxetine, bupropion, topiramate or ecopipam.
Suitable antidiabetics comprise insulin, GLP-1 (glucagon like peptide-1) derivatives such as those disclosed in WO 98/08871 to Novo Nordisk A/S, which is incorporated herein by reference as well as orally active hypoglycaemic agents.
The orally active hypoglycaemic agents preferably comprise imidazolines, sulphonylureas, biguanides, meglitinides, oxadiazolidinediones, thiazolidinediones, insulin sensitizers, xcex1-glucosidase inhibitors, agents acting on the ATP-dependent potassium channel of the xcex2-cells eg potassium channel openers such as those disclosed in WO 97/26265, WO 99/03861 and WO 00/37474 (Novo Nordisk A/S) which are incorporated herein by reference, nateglinide, glucagon antagonists such as those disclosed in WO 99/01423 and WO 00/39088 (Novo Nordisk A/S and Agouron Pharmaceuticals, Inc.), which are incorporated herein by reference, GLP-1 agonists such as those disclosed in WO 00/42026 (Novo Nordisk A/S and Agouron Pharmaceuticals, Inc.), which are incorporated herein by reference, DPP-IV (dipeptidyl peptidase-IV) inhibitors, PTPase (protein tyrosine phosphatase) inhibitors, inhibitors of hepatic enzymes involved in stimulation of gluconeogenesis and/or glycogenolysis, glucose uptake modulators, GSK-3 (glycogen synthase kinase-3) inhibitors, compounds modifying the lipid metabolism such as antilipidemic agents, compounds lowering food intake, PPAR (peroxisome proliferator-activated receptor) and RXR (retinoid X receptor) agonists.
In one embodiment of the invention the present compounds are administered in combination with insulin.
In a further embodiment of the invention the present compounds are administered in combination with a sulphonylurea eg tolbutamide, glibenclamide, glipizide, glimepiride, glicazide or glyburide.
In another embodiment of the invention the present compounds are administered in combination with a biguanide eg metformin.
In yet another embodiment of the invention the present compounds are administered in combination with a meglitinide eg repaglinide or senaglinide.
In still another embodiment of the invention the present compounds are administered in combination with a thiazolidinedione eg troglitazone, ciglitazone, pioglitazone, rosiglitazone or the compounds disclosed in WO 97/41097, WO 97/41119, WO 97/41120, WO 00/41121 and WO 98/45292 (Dr. Reddy""s Research Foundation), which are incorporated herein by reference.
In still another embodiment of the invention the present compounds may be administered in combination with an insulin sensitizer eg such as those disclosed in WO 99/19313, WO 00/50414, WO 00/63191, WO 00/63192, WO 00/63193 (Dr. Reddy""s Research Foundation) and WO 00/23425, WO 00/23415, WO 00/23451, WO 00/23445, WO 00/23417, WO 00/23416, WO 00/63153, WO 00/63196, WO 00/63209, WO 00/63190 and WO 00/63189 (Novo Nordisk A/S), which are incorporated herein by reference.
In a further embodiment of the invention the present compounds are administered in combination with an xcex1-glucosidase inhibitor eg miglitol or acarbose.
In another embodiment of the invention the present compounds are administered in combination with an agent acting on the ATP-dependent potassium channel of the xcex2-cells eg tolbutamide, glibenclamide, glipizide, glicazide or repaglinide.
In yet another embodiment of the invention the present compounds may be administered in combination with nateglinide.
In still another embodiment of the invention the present compounds are administered in combination with an antilipidemic agent eg cholestyramine, colestipol, clofibrate, gemfibrozil, lovastatin, pravastatin, simvastatin, probucol or dextrothyroxine.
In another aspect of the invention, the present compounds are administered in combination with more than one of the above-mentioned compounds eg in combination with metformin and a sulphonylurea such as glyburide; a sulphonylurea and acarbose; nateglinide and metformin; acarbose and meformin; a sulfonylurea, metformin and troglitazone; insulin and a sulfonylurea; insulin and metformin; insulin, metformin and a sulfonylurea; insulin and troglitazone; insulin and lovastatin; etc.
Furthermore, the present compounds may be administered in combination with one or more antihypertensive agents. Examples of antihypertensive agents are xcex2-blockers such as alprenolol, atenolol, timolol, pindolol, propranolol and metoprolol, ACE (angiotensin converting enzyme) inhibitors such as benazepril, captopril, enalapril, fosinopril, lisinopril, quinapril and ramipril, calcium channel blockers such as nifedipine, felodipine, nicardipine, isradipine, nimodipine, diltiazem and verapamil, and xcex1-blockers such as doxazosin, urapidil, prazosin and terazosin. Further reference can be made to Remington: The Science and Practice of Pharmacy, 19th Edition, Gennaro, Ed., Mack Publishing Co., Easton, Pa., 1995.
It should be understood that any suitable combination of the compounds according to the invention with diet and/or exercise, one or more of the above-mentioned compounds and optionally one or more other active substances are considered to be within the scope of the present invention.
The compounds of the invention may be administered alone or in combination with pharmaceutically acceptable carriers or excipients, in either single or multiple doses. The pharmaceutical compositions according to the invention may be formulated with pharmaceutically acceptable carriers or diluents as well as any other known adjuvants and excipients in accordance with conventional techniques such as those disclosed in Remington: The Science and Practice of Pharmacy, 19th Edition, Gennaro, Ed., Mack Publishing Co., Easton, Pa., 1995.
The pharmaceutical compositions may be specifically formulated for administration by any suitable route such as the oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), transdermal, intracisternal, intraperitoneal, vaginal and parenteral (including subcutaneous, intramuscular, intrathecal, intravenous and intradermal) route, the oral route being preferred. It will be appreciated that the preferred route will depend on the general condition and age of the subject to be treated, the nature of the condition to be treated and the active ingredient chosen.
Pharmaceutical compositions for oral administration include solid dosage forms such as capsules, tablets, dragees, pills, lozenges, powders and granules. Where appropriate, they can be prepared with coatings such as enteric coatings or they can be formulated so as to provide controlled release of the active ingredient such as sustained or prolonged release according to methods well known in the art.
Liquid dosage forms for oral administration include solutions, emulsions, suspensions, syrups and elixirs.
Pharmaceutical compositions for parenteral administration include sterile aqueous and non-aqueous injectable solutions, dispersions, suspensions or emulsions as well as sterile powders to be reconstituted in sterile injectable solutions or dispersions prior to use. Depot injectable formulations are also contemplated as being within the scope of the present invention.
Other suitable administration forms include suppositories, sprays, ointments, cremes, gels, inhalants, dermal patches, implants etc.
A typical oral dosage is in the range of from about 0.001 to about 100 mg/kg body weight per day, preferably from about 0.01 to about 50 mg/kg body weight per day, and more preferred from about 0.05 to about 10 mg/kg body weight per day administered in one or more dosages such as 1 to 3 dosages. The exact dosage will depend upon the frequency and mode of administration, the sex, age, weight and general condition of the subject treated, the nature and severity of the condition treated and any concomitant diseases to be treated and other factors evident to those skilled in the art.
The formulations may conveniently be presented in unit dosage form by methods known to those skilled in the art. A typical unit dosage form for oral administration one or more times per day such as 1 to 3 times per day may contain of from 0.05 to about 1000 mg, preferably from about 0.1 to about 500 mg, and more preferred from about 0.5 mg to about 200 mg.
For parenteral routes, such as intravenous, intrathecal, intramuscular and similar administration, typically doses are in the order of about half the dose employed for oral administration.
The compounds of this invention are generally utilized as the free substance or as a pharmaceutically acceptable salt thereof. One example is an acid addition salt of a compound having the utility of a free base. When a compound of the formula (I) contains a free base such salts are prepared in a conventional manner by treating a solution or suspension of a free base of the formula (I) with a chemical equivalent of a pharmaceutically acceptable acid, for example, inorganic and organic acids. Representative examples are mentioned above. Physiologically acceptable salts of a compound with a hydroxy group include the anion of said compound in combination with a suitable cation such as sodium or ammonium ion.
For parenteral administration, solutions of the novel compounds of the formula (I) in sterile aqueous solution, aqueous propylene glycol or sesame or peanut oil may be employed. Such aqueous solutions should be suitable buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose. The aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. The sterile aqueous media employed are all readily available by standard techniques known to those skilled in the art.
Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solution and various organic solvents. Examples of solid carriers are lactose, terra alba, sucrose, cyclodextrin, talc, gelatine, agar, pectin, acacia, magnesium stearate, stearic acid or lower alkyl ethers of cellulose. Examples of liquid carriers are syrup, peanut oil, olive oil, phospholipids, fatty acids, fatty acid amines, polyoxyethylene or water. Similarly, the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax. The pharmaceutical compositions formed by combining the novel compounds of the formula (I) and the pharmaceutically acceptable carriers are then readily administered in a variety of dosage forms suitable for the disclosed routes of administration. The formulations may conveniently be presented in unit dosage form by methods known in the art of pharmacy.
Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules or tablets, each containing a predetermined amount of the active ingredient, and which may include a suitable excipient. These formulations may be in the form of powder or granules, as a solution or suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion.
If a solid carrier is used for oral administration, the preparation may be tabletted, placed in a hard gelatine capsule in powder or pellet form or it can be in the form of a troche or lozenge. The amount of solid carrier will vary widely but will usually be from about 25 mg to about 1 g. If a liquid carrier is used, the preparation may be in the form of a syrup, emulsion, soft gelatine capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution.
A typical tablet, which may be prepared by conventional tabletting techniques, may contain:
If desired, the pharmaceutical composition of the invention may comprise the compound of the formula (I) in combination with further pharmacologically active substances such as those described in the foregoing.
The preparation of the compounds of this invention can be realised in many different ways. The starting imidazole derivatives of the formula (II) may be prepared according to procedures described in literature (see eg Croat. Chem. Acta. 1973, 45, 297. J. Am. Chem. Soc. 1976, 98, 984). The other reactants are either known compounds or compounds, which may be prepared in analogy with the preparation of similar known compounds.
Method A
Compounds of the formula (Ia), wherein m, n and p are as defined for formula (I) and V is aryl or heteroaryl, which may optionally be substituted as defined for formula (I), may be prepared as outlined below: 
The alcohol of a compound of the formula (II) wherein m, n and p are as defined above and Pg represents a protecting group like eg triphenylmethyl (trityl) may be reacted with a compound of the formula (III) wherein V is as defined above. This reaction is carried out in the presence of a catalyst like eg triphenylphosphine and a base like eg diethyl azodicarboxylate in a suitable solvent like eg THF at a temperature of up to reflux for the solvent used for eg 1-200 hours. Removal of the trityl group of a compound of the formula (IV) is accomplished with dilute acid to give a compound of the formula Ia).
Method B
Compounds of the formula (Ib), wherein m, n, p and V are as defined for formula (I), may be prepared as outlined below: 
A compound of the formula (V) wherein m, n and p are as defined above and Pg represents a protecting group like eg triphenylmethyl (trityl) and L represents a leaving group such as eg halogen or mesylate may be reacted with a compound of the formula (VI) wherein V and q are as defined above. This reaction is carried out in the presence of a strong base like eg sodium hydride in a suitable solvent like eg THF or DMF at a temperature of up to reflux for the solvent used for eg 1-200 hours. Removal of the trityl group from a compound of the formula (VII) is accomplished with dilute acid to give a compound of the formula (Ib).
Method C
A compound of the formula (Ic), wherein m, n, p, q, and V are defined as in formula (I), may be prepared as outlined below: 
An alcohol of the formula (II), wherein m, n, and p are defined as in formula (I) and PG is a suitable protecting group as is described in the literature (eg T. W. Greene, P. G. M. Wuts, Protective groups in organic synthesis, 2nd edition, John Wiley and Sons, Inc., New York) such as eg triphenylmethyl may be reacted with a suitable base such as eg sodium hydride, potassium hydride, lithium hydride in a suitable solvent such as tetrahydrofuran, ether or a hydrocarbon such as toluene or hexane. Successively a halogenide such as a bromide as shown in formula (VIII) or a chloride as shown in formula (IX) or a synthetic equivalent thereof may be reacted with the intermediate. Catalysts such as tetrabutylammonium iodide may be added optionally. The reaction temperature might be between xe2x88x9278xc2x0 C. and the boiling point of the solvent applied for a reaction time of 0.5-200 hours. Removal of the protection group of a compound of the formula (X) may be accomplished as described in the literature (eg T. W. Greene, P. G. M. Wuts, Protective groups in organic synthesis, 2nd edition, John Wiley and Sons, Inc., New York) eg a triphenylmethyl group may be removed with acid, such as acetic acid which may be diluted with another solvent such as water at a temperature between room temperature and 100xc2x0 C.
Method D
A compound of the formula (Id), wherein n, m, p, q, X, Y, and V are defined as in formula (I), may be prepared as outlined below: 
A cyclic ketone, of formula (XI) in which n, m, p, q and V are defined as in formula (I), and L is a leaving group such as bromo, chloro, or methansulfonyl, may be warmed with DMF to a suitable temperature such as a temperature between 100xc2x0 C. and 200xc2x0 C. for a time between 0.5 and 200 hours.
The present invention is further illustrated by the following representative examples, which are, however, not intended to limit the scope of the invention in any way.